While HSCT is an effective therapy, its use is associated with substantial risks, such as GVHD. Strategies to reduce GVHD have been the subject of numerous trials, but efforts have been incompletely effective and novel approaches are needed. The cytotoxicity of methotrexate is an important adjunct to calcineurin inhibition, but its intrinsic toxicity prolongs time to count recovery and increases toxicity. The objective of this project is to study two new approaches to GVHD control. The first takes advantage of the synergism between of siro!imus and tacrolimus. By using low doses of these drugs, it may be possible to control GVHD and to reduce transplant-related mortality. Pilot studies in high risk patients show a promising GVHD control and minimal toxicity. The second combines two promising approaches in matched sibling HSCT: 1) the use of mobilized PBSC as an alternative to marrow stem cells to speed engraftment and 2) T cell depletion (TCD) to reduce GVHD. Randomized trials of PBSCT show that survival can be improved perhaps due to more rapid engraftment, more graft-v-leukemia (GVL), and more complete immunologic recovery. However, there is a higher risk of acute and especially chronic GVHD. Interest in TCD waned, as it appeared that the loss of GVL was a serious limitation. GVL can be restored with donor lymphocyte infusions, but at significant risk of GVHD. Preliminary studies show that depletion of PBSC of CD8+ T cells is feasible with an excellent engraftment and controllable GVHD. This observation leads to the hypothesis that PBSCT using CD8 depleted PBSC will result in improved outcomes by maintaining the benefits of unmanipulated PBSCT with less GVHD. The specific aims of this proposal are: 1) to perform studies of the combination of sirolimus, tacrolimus, with or without low dose methotrexate in unrelated donor and family-member transplantation. The goal will be to eliminate MTX and maintain GVHD control and GVL; 2) to study PBSCT depleted of CD8+ T cells using a nickel bead-conjugated anti-CD8 product (CD8-HDM) in matched sibling and unrelated donor transplantation; and 3) to study the use of sirolimus, tacrolimus, and low dose methotrexate after non-myeloablative transplantation. All of these projects will be associated with studies of quality of life, chimerism, and immune recovery. Data will be collected from a well-studied cohort to facilitate correlations of chemokine use, and identification of minor histocompatibility antigens that are important in GVHD. Long-term plans are to provide the platform for phase II randomized trials as well as interventions based on data in obtained in the other projects.